Menopause reflects the loss of function of the ovaries which affects all women at certain ages of their lifetimes. It typically begins naturally in middle age (late 40s through early 50s) over a period of time. However, menopause may occur more abruptly and earlier in certain medical conditions or when induced through surgical removal of the ovaries. The natural symptoms of menopause usually begin slowly, during a phase described as menopausal transition or perimenopause, and can be devastating. These menopausal symptoms include irregular menses, hot flashes and night sweats, sleep disruption, atrophy of reproductive tissues, increased stress, tenderness of the breast, vaginal dryness, mood changes, forgetfulness, and sometimes osteoporosis and heart disease.
One of the most prevalent symptoms is the typical “hot flash” which is a woman's perception of a sudden increase in body temperature. The hot flash is the result of vascular changes which permit rapid increased blood flow through vessels. During a hot flash, the body temperature rises rapidly and then only slowly returns to its normal body temperature.
Various methods have been used to treat menopausal symptoms, and in particular, hot flashes. Hormonal Replacement Therapy (HRT) is a form of treatment which supplements naturally occurring hormones in the body. At normal levels, estrogen and progestin counter the effects of other hormones, such as luteinizing hormone (LH) and follicle stimulating hormone (FSH). During menopause, as estrogen and progestin levels are reduced, and levels of LH and FSH are found at high levels and menopausal symptoms become more apparent. [http://en.wikipedia.org/wiki/Menopause (accessed Feb. 2, 2012)]. HRT treatment aims to supplement levels of estrogen and progestin to reduce levels of LH and FSH and thus reduce menopausal symptoms.
Increased levels of estrogen, though, create a risk of a number of other health risks including cancer, heart attack, and strokes. [Decline in use of hormone therapy among postmenopausal women in the United Kingdom, Menopause 14 (3 Pt 1): 462-7; Differences in menopausal hormone therapy use among women in Germany between 1998 and 2003, BMC Womens Health 7: 19; Prescribing of hormone therapy for menopause, tibolone, and bisphosphonates in women in the UK between 1991 and 2005, Eur. J. Clin. Pharmocol. 63 (9): 843-9]. Accordingly, HRT treatment may create potentially undesirable consequences far more devastating that the effects of menopausal symptoms, such as stimulating the growth of malignant cells.
Use of selective serotonin re-uptake inhibitors (SSRIs) is another method which has been used to treat menopausal symptoms. SSRIs have typically been used as antidepressants. SSRIs increase levels of serotonin by inhibiting its re-uptake into presynaptic cells. In theory, by increasing the levels of serotonin in the brain, the claimed benefits achieved as an anti-depressant, i.e. improving mood and promoting sleep, also serve to alleviate menopausal symptoms. However, the efficacy of SSRIs has been disputed. [Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature, PLoS Medicine 2 (12): e392].
Selective Estrogen Receptor Modulators (SERMs) is another category of drugs which have been used to treat menopausal symptoms. These drugs act as agonists or antagonists to estrogen receptors throughout the body. However, it has been reported that most SERMs actually increase hot flashes. [http://en.wikipedia.org/wiki/Menopause (accessed Feb. 2, 2012). See also Menopausal Symptoms, Clin. Exp. Obstet. Gynecol. 31 (2): 123-6]. Other drugs such as anti-seizure medications (i.e., gabapentin), and blood pressure medications (i.e., clonidine), have also been used to treat menopausal symptoms. [http://en.wikipedia.org/wiki/Menopause (accessed Feb. 2, 2012)]. The mechanism of action of these agents is poorly understood, and the effectiveness of these treatments is disputed. [Gabapentin for hot flashes in 420 women with breast cancer: a randomized double-blind placebo-controlled trial, Lancet. 366(9488):818-24; Positive efficacy data from a phase 2 trial of gabapentin extended-release in the treatment of menopausal hot flashes, Menopause, 15(6): 1225; Nonhormonal Therapies for Menopausal Hot Flashes: Systematic Review and Meta-analysis, JAMA, 295(17):2057-71].
Natural regulation of menstrual cycles is controlled by complex interactions between various hormones and hormone producing glands within the body. The hypothalamus in the brain is a primary regulator of menstrual cycles. Hormones produced by the hypothalamus in the regulation of menstrual cycles include dopamine and prolactin. Dopamine inhibits the release of prolactin, while Thyrotropin Releasing Hormone (TRH) promotes the release of prolactin. Dopamine receptors in the body may be grouped into categories producing different effects depending on the type of receptor to which dopamine binds. Receptors of groups D2, D3, or D4 produce effects contrary to those of group D1 and D5. [D2 Dopamine receptor subtype mediates the inhibitory effect of dopamine on TRH-induced prolactin release from the bullfrog pituitary, Gen. Comp. Endocrinology, 168(2):287-92; Dopamine D1 receptor analogues act centrally to stimulate prolactin secretion in ewes, J. Endocrinology, 137:457-64]. Dopamine binding to receptors D2, D3, or D4 in the hypothalamus will inhibit the production of prolactin, and also inhibit the pulsatile production of Gonadotropin Releasing Hormone (GnRH) in estrogen deficient females [Regulation of Gonadotropin-Releasing Hormone (GnRH)-Receptor Gene Expression in Tilapia: Effect of GnRH and Dopamine, Biology of Reproduction, 70:1545-51]. It is the latter effect which in turn inhibits the production of LH and FSH in the pituitary gland in the estrogen deficient state of perimenopause and menopause. LH and FSH stimulate various functions in the reproductive and menstrual cycles. To the contrary, dopamine binding to the D1 and D5 receptors will stimulate the production of prolactin and will increase the production of GnRH thus leading to an increase in hot flashes. [D2 Dopamine receptor subtype mediates the inhibitory effect of dopamine on TRH-Induced prolactin release from the bullfrog pituitary, Gen. Comp. Endocrinology, 168(2):287-92].
LH and FSH are found at high levels during menopause. When levels of estrogen are higher, prior to menopause, estrogen provide a feedback loop which serves to limit the production of LH and FSH. However, during menopause, when levels of estrogen drop, levels of LH and FSH increase. Studies have shown that LH and FSH act as vasodilators which increase the flow of blood throughout the vessels. The increase in the flow of blood causes symptoms of hot flashes.
Drugs which activate a receptor to produce a pharmacological response are called agonists. These drugs may mimic the effect of the naturally occurring substance. An antagonist counteracts the pharmacological effect of a drug or a naturally occurring substance. U.S. Pat. No. 7,645,750 describes the use of certain drugs in the treatment of menopausal symptoms, in particular, hot flashes. In particular, the patent describes the use of risperidone, quetiapine, clozapine, olanzapine, aripiprazole, ziprasidone, zotepine, or 9-hydrozyrisperidone as serotonin type 2A (5-HT2A) and dopamine type 2 (D2) receptor antagonists. However, the efficacy of administering these drugs to treat menopausal symptoms has been disputed. [The Safety of Verlipride, Expert Opin. Drug Saf. 5(5):695-71]. As is discussed herein, the subject invention describes treatment with a dopamine agonist to provide relief of menopausal symptoms. Accordingly, it follows that treatment with a dopamine antagonist provides contrary results.
Ropinirole™ is a dopamine agonist manufactured by GlaxoSmithKline, Cipla, and Sun Pharmaceutical. The chemical formula for Ropinirole is 4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one as follows:
Ropinirole has typically been used in the treatment of Parkinson's disease. It has also been used to treat Restless Legs Syndrome. Ropinirole has high affinity to D2, D3, or D4 dopamine receptors with the highest affinity for D2. [Preclinical Pharmacology of Ropinirole (SK&F 101468-A) a Novel Dopamine D2 Agonist, Pharmacology Biochemistry & Behavior 38: 147-154]. However, Ropinirole has not previously been studied or used in the treatment of menopausal symptoms except by the inventor as discussed herein to illustrate the utility of the subject invention.
The other symptom after hot flashes that Is equally, if not more, damaging to the daily functioning of a menopausal woman is sleep deprivation. Tizanidine is the molecule that can most effectively address this symptom. Tizanidine™ (a/k/a Zanaflex™), chemical formula 5-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)benzo[c][1,2,5]thiadiazol-4-amine, is a drug compound which has traditionally been used as a muscle relaxant. The molecular structure of Tizanidine is as follows:
As such, it has been used in the treatment of disorders such as multiple sclerosis, spastic diplegia, back pain, and other problems related to the spine and central nervous system. [A Practical Overview Of Tizanidine Use For Spasticity Secondary To Multiple Sclerosis, Stroke, And Spinal Cord Injury, Curr Med Res Opin 24(2):425-39]. Tizanidine is also an excellent sedative [http://en.wikipedia.org/wiki/Tizanidine (accessed Jan. 8, 2012)]. Tizanidine has not previously been considered or used in the treatment of menopausal symptoms of sleep disturbance except by the inventor as discussed herein to Illustrate the benefits of the subject invention.
Given the risk of some of the current methods of treatment, and the failure of those methods to adequately treat and control menopausal symptoms such as hot flashes and sleep deprivation, there remains a need for improved means of addressing and treating these symptoms. The subject invention addresses these concerns and provides a new combination of drugs and methods of use which previously have not distinctly been shown to reduce the severity of hot flashes and menopausal symptoms of sleep disruption.